Spontaneously occurring lymphoma in the dog has many of the same histopathological, molecular, and clinical features as non-Hodgkin's lymphoma (NHL) in people [1-3]. Most of the lymphoma subtypes recognized in humans have histopathologically identical counterparts in the dog [4] and recent investigations show similar molecular characteristics in the two species [1,5]. Likewise, spontaneous lymphoma in the dog has a similar clinical presentation, response to chemotherapy, and clinical progression compared to NHL in people [1-3]. Given these similarities and the advantage of larger subject size and presence of spontaneous disease (in contrast to small subject size and experimentally induced disease in rodents), spontaneously occurring lymphoma in the dog represents an excellent large animal model for the study of lymphoma in people, including investigation of new therapeutic agents [1-3].
Laboratory study of spontaneous canine lymphoma has been severely limited by the lack of validated, well characterized, and widely disseminated cell lines. Those previously reported were either only partially characterized, were not widely distributed, or were established from leukemias, rather than lymphomas [6-9]. As in humans, establishment of new lymphoma cell lines is difficult.
In addition, despite the high incidence of lymphoma in the dog, there are relatively few reports documenting the successful establishment of cell lines from spontaneously occurring lymphoma in the dog. Those reported were either only partially characterized, not widely distributed, or established from leukemias, rather than lymphomas [6-9]. Establishment of cell lines from human leukemia/lymphomas not associated with viral etiologies (e.g., EBV, HTLV-1) is difficult (no transforming lymphotropic viruses such as EBV or HTLV-I have been conclusively identified in dogs), and most attempts fail [48]. Furthermore, many more leukemia cell lines than lymphoma cell lines have been established [48, 49]. Factors that have been proposed to enhance success in establishing leukemia/lymphoma cell lines include primary tumor cell source (“liquid” tumors and effusions being more successful), subject remission status (previous chemotherapy, relapsed tumors being more successful), and culture conditions (high CO2, high serum concentrations, addition of growth factors, e.g. IL-2, IL-3, IL-6, GCSF, GM-CSF, SCF, or conditioned medium) improving success [49].
Lymphoma is the most common life-threatening cancer of dogs, accounting for up to 24% of all malignancies and over 80% of all hematopoietic cancers [50, 51]. Dogs develop virtually all subtypes of sporadic NHL seen in humans and are at greater relative risk. Furthermore, the relative risk for this disease in some breeds is up to four times higher than the average for all dogs [11, 52], suggesting that heritable risk factors for the disease have been firmly established in the derivation of specific breeds. Untreated cases, especially those of high-grade type, rarely survive beyond three months after diagnosis, but the disease is generally responsive to standard of care using CHOP-based chemotherapy protocols, increasing both the length and quality of affected dogs' lives [3].
With standard of care, remission can be achieved in >85% of canine NHL cases, and median survival ranges between 9 and 12 months [53]. This represents approximately 10% of an average canine lifetime, thus providing a tremendous opportunity to investigate new treatments in a biologically relevant large animal model. Importantly, the completion of a high (7.5×) coverage canine genome [54] has paved the way for the development of critical resources that will allow the integration of naturally occurring canine lymphoma and other cancers within the mainstream of cancer research.
By combining advances in canine genomics, establishment of canine cancer cell lines and xenograft mouse models, and initiation of clinical trials of new anticancer treatments in dogs with cancer, the study of spontaneously occurring lymphoma and other cancers in the dog will assist the development of new anticancer agents and help guide early human trials.
Therefore, there is a need to develop cell lines that can be used to study lymphoma and for developing treatments of lymphomas.
Considering the above-mentioned, there is a need for therapeutic strategies to treat lymphomas in mammals, and in particular, in canine and in humans.
Until the present invention, there have been no reports for the establishment of canine lymphoma cells or cell lines.